Tumor necrosis factor-α (hereinafter, TNF) is a multifunctional pro-inflammatory cytokine secreted predominantly by monocytes/macrophages that has effects on lipid metabolism, coagulation, insulin resistance, and endothelial function. TNF is a soluble homotrimer of 17 kD protein subunits. A membrane-bound 26 kD precursor form of TNF also exists. It is found in synovial cells and macrophages in tissues. Cells other than monocytes or macrophages also produce TNF. For example, human non-monocytic tumor cell lines produce TNF as well as CD4+ and CD8+ peripheral blood T lymphocytes and some cultured T and B cell lines produce TNF. It is involved in, but not unique to, rheumatoid arthritis, and occurs in many inflammatory diseases. Receptors for TNF are on several mononuclear cells, in the synovial membrane, as well as the peripheral blood and synovial fluid. TNF is a critical inflammatory mediator in rheumatoid arthritis, and may therefore be a useful target for specific immunotherapy.
TNF causes pro-inflammatory actions which result in tissue injury, such as degradation of cartilage and bone, induction of adhesion molecules, inducing pro-coagulant activity on vascular endothelial cells, increasing the adherence of neutrophils and lymphocytes, and stimulating the release of platelet activating factor from macrophages, neutrophils and vascular endothelial cells. Recent evidence associates TNF with infections, immune disorders, neoplastic pathologies, autoimmune pathologies and graft-versus-host pathologies.
TNF is believed to play a central role in gram-negative sepsis and endotoxic shock, including fever, malaise, anorexia, and cachexia. Endotoxin strongly activates monocyte/macrophage production and secretion of TNF and other cytokines. TNF and other monocyte-derived cytokines mediate the metabolic and neurohormonal responses to endotoxin. Endotoxin administration to human volunteers produces acute illness with flu-like symptoms including fever, tachycardia, increased metabolic rate and stress hormone release. Circulating TNF increases in patients suffering from gram-negative sepsis. Neutralizing antisera or monoclonal antibodies to TNF have been shown in mammals to abrogate adverse physiological changes and prevent death after lethal challenge in experimental endotoxemia and bacteremia.
Thus, TNF has been implicated in inflammatory diseases, autoimmune diseases, viral, bacterial and parasitic infections, malignancies, and/or neurodegenerative diseases and is a useful target for specific biological therapy in diseases, such as rheumatoid arthritis and Crohn's disease. Beneficial effects in open-label trials with a chimeric monoclonal antibody to TNF have been reported with suppression of inflammation and with successful re-treatment after relapse in rheumatoid arthritis and in Crohn's disease.
Adalimumab (also known by its trademark HUMIRA® available from Abbott Laboratories) is a recombinant human monoclonal antibody specific for TNF-α. This monoclonal antibody binds to TNF and blocks its interaction with the p55 and p75 cell-surface TNF receptors. See, U.S. Pat. No. 6,090,382, the entire teaching of which is incorporated herein by reference.
As previously stated, TNF plays a significant role in the pathological inflammatory process. Adalimumab is clinically used to treat pathological inflammatory processes such as rheumatoid arthritis. For clinical applications and scientific research there is a need to have binding proteins, such as antibodies, capable of binding specifically to adalimumab. In the clinical setting, subjects receiving adalimumab may experience an adverse response due to, e.g., excessive adalimumab or an unusual sensitivity toward the antibody. In some cases, patients who are under adalimumab treatment might contract a serious infection where biologically active TNF is essential for the control of the infection. Further, in order to investigate adalimumab and its role in the treatment of certain pathologies it is necessary to qualitatively and quantitatively examine adalimumab in a sample matrix. The present provides binding proteins specific for adalimumab which can be used to effectuate these goals.